The long term objective of this proposal is the elucidation of the structural and conformational features necessary for activity at specific opioid receptors with major emphasis placed upon the delta opioid receptor. Such elucidation, in addition to furthering our understanding of the molecular basis of opioid action, would greatly aid the design of analogs with more selective pharmacological actions which may prove to be a great clinical significance. The proposed approach for achieving this objective involves the synthesis, pharmacological evaluation, and conformational analysis of rationally designed analogs related to three highly delta receptor selective opioid peptides which have been developed by the principal investigator. Additionally, a structurally related analog which represents a significant lead toward mu receptor selectivity will be pursued. Correlation, among these series of analogs, of opioid activity with structure and conformation will allow the determination of those key features consistent with activity at a specific opioid receptor. Conformational analyses will rely heavily on modern NMR techniques. In order to utilize the full informational content available from these NMR experiments, it will be necessary to incorporate stereospecifically deuterated amino acids so as to allow complete assignment of resonances arising from diasteriotopic protons (or carbons) in the peptides studied. Of particular importance will be the measurement of interproton nuclear Overhauser effects (NOE) and the determination of interproton distances from these NOEs. These distances will then be utilized as constraints for distance geometry calculations of conformations consistent with the NMR data. Energy minimization of structures constrained to adhere to these interproton distances as well as unconstrained structures will be performed. Comparison of the energies of these structures will address the reasonableness of the approach and may provide insight into binding energetics.